Process for preparing z-amino-x



"Patented Dec. 10, 1930' v 2.22am rnocsss ron rnsrmmo z-amo-scnnonoJackson 2. English, Stamford, com. mm to American Oyanamid Company, NewYork. N. 2., acorporation ofllaine No Drawing. Application August-6,194.,

Serial No. 851,848

scum. Y 260-251) This invention relates to an improved process ofproducing 2-amino-4-chloropyrimidine.

A class 01 chemotherapeutic compounds which shows very great promise inthe treatment of infectious diseases comprises those recently producedby the condensation of sulfanilamide andamino pyrimidines to form thecorresponding sulfanilamido pyrimidines. Some of the outstanding membersof this class of compounds are those produced by the condensation ofsulfanilamide with 2-amino-pyrimidines, 2-amino pyrimidine itself andthe 2-amino substituted pyrimidines including2-amino-5-chloropyrimidine.

The present invention provides an improved process for the production ofZ-amino-i-chloropfiimidine which comprises the reaction of2-amino-4-hydroxy-pyrlmidine sulfate or isocytosine sulfate withphosphorous oxychloride. It has been proposed 2-a'mino-4-chlorop dinefrom isocytosine by reacting with phosphorus oxychloride; The prior.proposed process, however, has not been entirely satisfactory in thatthe yields are only about 40% of the theory. when the process of thepresent invention is employed using isocytosine sulfate, the yields arevery much larger being on the average of about 70 to 80% of. the theory.

'I'hepresent invention is not particularly concerned with the methodbywhich the isocytosine sulfate is produced and it may be produced by anysuitable process. improved process for the preparation of isocytosineinvolving .the condensation of guanidine salts withcrude mixtures con-'crude isocytosine 'with dilute sulfuric 'acid and filtration whichresults in the removal of impurithe in the filtrate leaving the purifiedisocytosine sulfate as a residue. Y

It is not necessary that a very pure isocytosine sulfate be used incarrying out the present invenis an advantage of the presentinvention-,however. Y he when pureisocytosine suifateiis used; a verypure fi aniino d-chioropyrimidine is. produced process pyrimidine but itis not limited to the details the past to produce suitable forcondensation with acetylsulianilyi chloride to produce achemotherapeutic product. The present invention is based on my discoverythat the use of isocytosine sulfate-in reactions with phosphoruscxychloride results in a smoother 5 reaction, improved yields and aproduct of higher quality than is obtained when isocytosine is used asthe reactant.

--'11ne invention will be described in greater-detail in conjunctionwith the iollowing specific ex- 10 amples which are illustrative of thepresent for the production of 2-amino-4-chlorotherein set forth. Theparts are by weight except for liquids where the corresponding parts by15 volume are used.

' Example 1 624 parts of isocytosine sulfate are suspended 20 in1900'parts of phosphorus oxychlori'de and thewhole is refluxed gentlyfor three and one-hall. hours. At the end of this period the reactionmixture is a clear, light-brown liquid. 930.-parts of phosphorusoxychloride are distilled oil! .in 25 vacuum and the semi-viscousresidue is poured with stirring into 3500 parts of ice and 1000 P r ofwater. 10 parts of decolorizlng charcoal and a few drops of ananti-foaming agent are added to the solution and the whole is stirrediortwo 30 hours. I v

The mixture is filtered and neutralized at room temperature bytheaddition 0! about 2850 parts of concen aqueous ammonia (28%). The

mother liquoris decanted from the nearly color- 35 less precipitate andthis is washed several times with water by decantation.

The 2-amino-i-chloropyrimidine was collected by nitration, pressedout-well and dried at 60 C.

The yield was 536 parts. J

Example? 267 parts of crude isocytosine produced by the condensation ofguanidlne with forniyl acetic acid and having a melting-point withdecomposition 5 at 253-255 C. are stirred.with about 500 parts of 10%sulfuric acid for about 45 minutes at room temperature. The mixture isthen hit ed,- v *the solid is washed well with water and dried at aboutco -c. The'yield 18 242 parts r l snt- 5 colo I e 'suliatemelting withdecomposition atflS-S'i'i' C. which is sufliciently pure for use as.-intermediate in the production of 2-amino A sample of theisocytosine wasreacted withphosphorus oitychloride' as described in Example 1. Theyield of 2-amino-4-ch1oropyrimidine was about 70%. What I claim is: a 1.A method of producing 2-amino-4-ch1oro- 5 pyrimidine which comprisesreacting phosphorus oxychloride with isocytosine sulfate.

2. A method of producing 2-amino-4-chloropyrimidine which comprisesrefluxing a mixture i of i'socytosine sulfate and phosphorusoxychloride. separating the reaction'product from the phosphorusoxychloride, dissolving the reaction product in water, filtering andneutralizing the filtrate with a base to precipitate the2-amino-4-chloropyrimidine.

, JACKSON P. ENGLISH.

